The use of antimicrobial compositions to help treat, prevent or control diseases of man and other animals is an integral part of modern medicine. Topical antimicrobial compositions are commonly used to help prevent the spread of disease from animals to man, from man to animals and between animals. Topical antimicrobial compositions are ubiquitous throughout modern society and are conveniently available, many times free of charge, in areas such as shopping centers, schools, and other public areas. Topical antimicrobial products may be in the form of lotions, gels, soap and shampoo, and other solutions; in the form of wipes or pads; or present as embedded in certain polymers or plastics.
The preservation of the active functions of ingredients (i.e., antibacterial, emollient, moisturizing, humectants, exfoliating) in complex systems is often problematic. That is, many active, therapeutic agents (especially those from natural origins) can be over-emulsified such that the benefit of the ingredient may be lost. For example, glyceryl monolaurate (GML) is a known, potent antimicrobial agent. However, it has very low solubility and is problematic is many aqueous and lipid based systems. Attempts to use GML in formulations via the addition of emulsifiers, however, typically result in a loss of desired product efficacy of GML, namely antimicrobial properties.
Topical antimicrobials have been shown to be effective in destroying bacteria, viruses, and certain fungi when applied appropriately. Typically, topical antimicrobials are applied directly to the skin or to surfaces wherein potential infective microorganisms may reside and present potential for transference from one animal to another.
In the United States, antimicrobial ingredients and products are governed by the US Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) depending upon the type of chemicals and intended use. The EPA provides regulatory guidance pursuant to the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) of 1947. Under FIFRA, no one may sell, distribute, or use a pesticide unless it is registered by the EPA, or it meets a specific exemption as described in the regulations. Registration includes approval by the EPA of the pesticide's label, which must give detailed instructions for its safe use. The EPA must classify each pesticide as either “general use,” “restricted use,” or both. “General use” pesticides may be applied by anyone, but “restricted use” pesticides may only be applied by certified applicators or persons working under the direct supervision of a certified applicator. Because there are only limited data for new chemicals, most pesticides are initially classified as restricted use. Applicators are certified by a state if the state operates a certification program approved by the EPA.
Antimicrobial ingredients and products intended for use on or in conjunction with animals, such as humans, fall under the jurisdiction of the FDA. The FDA considers the control of microorganisms found on the skin of individuals important to public health. The potential for the transmission of opportunistic pathogens to oneself or to others is significant, in the home, in institutional and commercial settings, as well as in healthcare settings. The risk of infection or acquisition of disease from the transmission of microorganisms can be correlated to specific tasks in all of these settings. The exposure and, consequently, the risk to populations of varying susceptibilities determine the ingredient performance desired and the attributes necessary to mitigate the risk.
The FDA, in 1978, found that the reduction of flora, both transient and resident, has been sufficiently supported to be considered a benefit. The agency has embraced the reduction of skin flora by a pre-specified amount as a valid surrogate end-point for the efficacy of topical over-the-counter (OTC) antimicrobial products. The Industry Coalition has concluded that the log reductions for non-professional antibacterial products are appropriate as cited by FDA in the Jun. 17, 1994 Tentative Final Monograph, 59 Fed. Reg. 31402 (TFM) (i.e., 2 log10), as long as standardized ASTM methods (with neutralization of all sampling fluids) are employed in the Final Monograph. In addition, the FDA mandates that topical antibacterial products should be effective the first time they are used, and effectiveness should be demonstrated after a single wash.
Per the FDA, today's generation of topical OTC antimicrobial products provide a public health benefit by reducing bacteria on skin. Such products are formulated with active ingredients that have the capability of reducing transient or resident organism populations with greater effectiveness and efficiency than can be achieved through the use of non-antimicrobial products. This additional reduction translates to risk reduction in the transmission of potentially pathogenic organisms and in the potential for disease acquisition (Breneman et al. 1998; Rose and Haas 1999).
In general, topical OTC antimicrobial products are designed to provide a prophylactic (i.e., preventive) benefit rather than a therapeutic benefit. The risks that are mitigated by topical OTC antimicrobial products are due to the acquisition of disease or illness from the transmission of transient organisms from oneself, others, or from environmental sources (e.g., fomites). In some cases reduction of resident flora may also be desirable (e.g., impetigo, eczema). These product attributes fully support the current OTC drug indication of “to decrease bacteria on skin” and translate into tangible public health benefits such as reductions in: the incidence of diarrhea; in skin/eye diseases; in illness rates (e.g., self-reported upper respiratory symptoms and secondary transmission of gastrointestinal illness); and in absenteeism due to infectious disease (e.g., colds, flu, gastrointestinal disease).
Topical OTC antimicrobial products are currently available in many forms that may or may not require a water rinse. Products used without water rinse include lotions, gels, sprays, liquids, and solid sticks. Products that require a water rinse include bars, shampoos, and soaps. Recently, solid wipe products have become popular and come in a variety of embodiments. These products usually contain a single antimicrobial ingredient. The type of composition is typically predicated by the application and includes aqueous, non-aqueous, oil in water, and water in oil emulsions.
There are many types of antimicrobial compositions that are generally recognized as safe (GRAS) include, but not limited to, ethyl alcohol, isopropyl alcohol, 2,4,4′-Trichloro-2′-hydroxydiphenyl ether (triclosan), benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bromochlorophene, chlorophene, didecyldimonium chloride, lauritrimonium chloride, myristalkonium saccharinate, shilkonin, sodium capryloamphoacetate, p-tertarylphenol, phenol, phenoxyethanol, etc. Also listed are both monoesters of edible fatty acids and polyhydric alcohols such as glycerol monolaurate and short to medium chained saturated fatty acids such as caprylic, capric, and lauric acids. In particular, the glycerol monoester of lauric acid (glycerol monolaurate or monolaurin) in combination with a chelating agent such as lactic acid is reported to be an effective antimicrobial system.
Even though glycerol monolaurate has been shown to be an effective broad range antimicrobial agent, low solubility and the formation of microcrystalline structures in situ have limited its use in applications. Glycerol monolaurate is typically used in concentrations in commercial formulations between 1-2%. Even at such low concentrations, formulations containing glycerol monolaurate are unstable such that the use of surfactants, emulsifiers, or other stabilizing agents is required.
Attempts to increase the solubility of glycerol monolaurate, and other fatty acids esters, diglycerides, triglycerides, etc. has been the focus of much research and development. It has been found by the inventors herein that many of the common emulsifying mechanisms, for example the use of surfactants and emulsifiers with various HLB values and combinations thereof, can render the active ingredient ineffective. That is, the act of emulsifying glycerol monolaurate with traditional emulsifiers results in a non-antimicrobial product. Thus the prior art has encountered a long-standing problem when attempting to include such anti-microbial agents as glycerol monolaurate at substantial concentrations while maintaining its anti-microbial effectiveness. The present invention addresses that long-standing problem by providing formulations of highly soluble, stable liquid crystal mixture of biologically active fatty acid esters (salts and/or glycerol(s)) in an anhydrous polyhydric alcohol system in which the anti-microbial action of the fatty acid esters is maintained. The present invention further provides for methods for the generation of such formulations.